Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis

Abstract

Cigarette smoking causes emphysema, a fatal disease involving extensive structural and functional damage of the lung. Using a guinea pig model and human lung cells, we show that oxidant(s) present in tobacco smoke not only cause direct oxidative damage of lung proteins, contributing to the major share of lung injury, but also activate Rtp801, a key proinflammatory cellular factor involved in tobacco smoke-induced lung damage. Rtp801 triggers nuclear factor κB and consequent inducible NOS (iNOS)-mediated overproduction of NO, which in combination with excess superoxide produced during Rtp801 activation, contribute to increased oxidonitrosative stress and lung protein nitration. However, lung-specific inhibition of iNOS with a iNOS-specific inhibitor, N6-(1-iminoethyl)-L-lysine, dihydrochloride (L-NIL) solely restricts lung protein nitration but fails to prevent or reverse the major tobacco smoke-induced oxidative lung injury. In comparison, the dietary antioxidant, ascorbate or vitamin C, can substantially prevent such damage by inhibiting both tobacco smoke-induced lung protein oxidation as well as activation of pulmonary Rtp801 and consequent iNOS/NO-induced nitration of lung proteins, that otherwise lead to increased proteolysis of such oxidized or nitrated proteins by endogenous lung proteases, resulting in emphysematous lung damage. Vitamin C also restricts the up-regulation of matrix-metalloproteinase-9, the major lung protease involved in the proteolysis of such modified lung proteins during tobacco smoke-induced emphysema. Overall, our findings implicate tobacco-smoke oxidant(s) as the primary etiopathogenic factor behind both the noncellular and cellular damage mechanisms governing emphysematous lung injury and demonstrate the potential of vitamin C to accomplish holistic prevention of such damage.cigarette smoke | emphysema | vitamin C | ascorbate | Rtp801

Induction of DDIT4 Impairs Autophagy Through Oxidative Stress in Dry Eye

“…19,20 DDIT4 has traditionally been recognized as an inhibitor of the mammalian target of rapamycin (mTOR) pathway and a regulator of cell survival and proliferation, 21 but recent studies have found that DDIT4 ablation diminishes tissue injury caused by oxidative stimuli, such as oxygeninduced retinopathy and cigarette smoke-induced lung damage. [22][23][24][25] Furthermore, it has been discovered that the overexpression of DDIT4 enhances susceptibility to oxidantinduced injuries and reduces exercise capacity. 26 These contradictory findings suggest that additional studies are necessary to elucidate the pathophysiological roles of DDIT4.…”

Association of MMP‐2 and MMP‐9 expression with recurrences in primary spontaneous pneumothorax

“…In the univariate analysis, the HR of overall recurrence in the age > 20 years group was 0.53 and that in the age ≤ 20 years group was 1.0 (Table 4), revealing that recurrence predominantly affects young patients with PSP. Exposure to cigarette smoking causes emphysema‐like symptoms, and is associated with oxidative DNA adduct formation, apoptosis, and bronchiolar inflammation [32–34]. However, our data showed no significant correlation between smoking status and MMP‐2 or MMP‐9 expression in PSP patients (Table 2).…”

Physalis peruviana L. inhibits airway inflammation induced by cigarette smoke and lipopolysaccharide through inhibition of extracellular signal-regulated kinase and induction of heme oxygenase-1

“…High levels of iNOS are associated with a variety of pathological conditions, including COPD (28). Gupta et al reported that CS exposure leads to iNOS expression, which results in production of toxic NO metabolites, leading to severe lung damage (29). The levels of COX-2 are significantly increased in small airway epithelium of patients with COPD, and the increase in the levels of this molecule contribute to airway remodeling and inflammation, which are major characteristics of COPD (30).…”